This application is made to renew a component of the Mouse Models of Human Cancer Consortium (MMHCC) that focuses on modeling myeloid malignancies in the mouse. These diseases represent a substantial burden, and current treatment strategies are unsatisfactory. During the initial period of support, the applicant team has largely achieved our research goals, which involve engineering and characterizing new and existing murine models of myeloid malignancies, exploiting retroviral insertional mutagenesis to perform forward genetic screens to identify genes that contribute to leukemia initiation and progression, developing new technologies and classification systems for analyzing mouse myeloid malignancies, and generating resources to benefit the entire mouse cancer modeling research community. We have also made substantial contributions to the MMHCC though participation in many of its activities. This renewal will build upon and extend this work through integrated experiments to: (1) utilize retroviral insertional mutagenesis to discover and interrogate novel genes that contribute to leukemogenesis in the context of known leukemia-associated genetic lesions;(2) harness mice with segmental deletions that model the losses of 5q31 and 7q22 found in human myeloid leukemia for gene discovery and functional studies;and, (3) harness cytogenetic analysis, SKY, and expression profiling to address specific questions relevant to the pathogenesis and treatment of murine and human myeloid malignancies. We are also fully committed to continuing to develop the MMHCC as a resource for the cancer research community. The applicant team is comprised on the same group of 6 investigators that are currently contributing to these studies and have developed a track record of highly productive research interactions.